The search for novel therapies for ischaemic-reperfusion injury in the heart has been a subject of intense research, both for recovery from open-heart surgery, where the limited capacity for the heart to survive ischaemia is a well researched problem (Stanley et al, 1997), and from the viewpoint of modulating the extent of damage incurred during episodes of cardiac ischaemia (Stanley et al, 1997). It is also well established that the incidence of coronary heart disease is a major factor in the morbidity and mortality of diabetic patients (Fuller et al, 1983; Hillier et al, 1988). There is also evidence that standard drugs for the treatment of diabetes of the sulphonylurea group may have negative effects, including those on K+ channel function (smits & Thien, 1995; Muhlhauser et al, 1997).
The complexity of the events following ischaemia-reperfusion is such that there is a very wide ranging database of potential therapeutic and cardioplegic agents targeting differing aspects of the cascade leading to damage to cardiac function. It has been apparent from work as early as the 1960s (Danforth et al, 1960; Berne, 1963) to the present (Zimmer, 1996; Houston et al, 1997) that a key feature of the cascade of interlinked biochemical events following ischaemic-reperfusion injury centres on the loss of adenine nucleotides from the myocardium. There is, thus, an absolute requirement for the restitution of the intracellular ATP concentration and the energy charge of the cell in order to restore normal cardiac function.
Adenine nucleotide synthesis can occur via utilization or reutilisation of adenine nucleotide breakdown products via the salvage pathway, or via de novo synthesis from small molecular weight precursors. The former is the most effective in terms of energy requirement (Mangano, 1997; Meldrum et al, 1997).
However, in addition to the requirement for the purine ring, a supply of phosphoribosylpyrophosphate (PRPP) is essential both for the salvage and de novo routes of synthesis; this latter compound is, in turn, subject to tight regulation and is dependent upon a supply of ribose-5-phosphate (Kunjara et al, 1987). Zimmer (1980) demonstrated that restitution of myocardial adenine nucleotides was accelerated by ribose, as was the normalisation of depressed heart function in rats (Zimmer, 1983). This author stated that “The advantage of ribose over other metabolic interventions is that is does not affect the haemodynamics of the heart with an ultimate change in oxygen demand and that is has no vasoactive properties which may result in afterload alterations”.
Recently, Zimmer (1996) reported that in two in vivo rat models, the overloaded and catecholamine-stimulated heart and the infarcted heart, the normalisation of the cardiac adenine nucleotide pool by ribose was accompanied by improvement in global heart function. Further, the combined treatment with ribose and adenine or inosine in isoproteronal-treated rats was more effective in the restoration and completely restored the ATP level within a shorter period of time than either treatment alone.